At a Glance

Multiple endocrine neoplasia type I (MEN1) is a syndrome of inherited predisposition to tumors of the parathyroid, pancreatic islets, and anterior pituitary gland. This syndrome, which is typically caused by germline mutations in the MEN1 gene, is diagnosed when a patient manifests at least two of these tumor types.

Family members of MEN1 patients are also at risk, since the approximately 85% of cases are inherited in an autosomal dominant fashion. The most common initial presentation is hyperparathyroidism, and hyperprolactinemia is also seen in a significant minority of patients. Pancreatic islet tumors may secrete gastrin, insulin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, or somatostatin. In addition to prolactinomas, adrenocorticotrophic hormone (ACTH) or growth hormone (GH)-producing pituitary adenomas may also be seen. Any one of these tumors in isolation is unlikely to represent MEN1, although as many as 38% of gastrinomas may be associated with the MEN1 syndrome.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Since hyperparathyroidism is the most common initial manifestation of this syndrome, parathyroid hormone (PTH) and serum calcium measurements (total and ionized) are an important diagnostic. Pancreatic islet tumors may secrete one of a number of hormones, and confirmatory measurement is indicated to follow up any suggestive clinical syndrome (gastrin for Zollanger-Ellison syndrome, insulin for fasting hypoglycemia, etc.).

Anterior pituitary lesions may be detected by imaging, as well as by measuring prolactin, ACTH, and GH levels. In addition to confirming this diagnosis in a patient who is exhibiting clinical symptoms of MEN1, screening family members is also an important component of early diagnosis and management. Current consensus suggests that screening of unaffected individuals at risk should occur annually by fasting measurement of calcium, PTH, gastrin, insulin, glucose, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, chromogranin A, prolactin, and IGF-1. Imaging-based screening should also be utilized every 1-3 years.(Table 1)

Table 1.

Test Results Indicative of the Disorder

Calcium, PTH

Pancreatic peptides (gastrin, insulin, VIP, etc.)

Prolactin, ACTH, IGF-1

MEN1 sequence testing

Elevated in hyperparathyroidism

Increased in malignancies from the corresponding precursor cells

One or more may be increased in the setting of pituitary adenoma

Mutation detected in ~80% of cases

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

DNA testing of the MEN1 gene is not affected by any medications. Fasting hormone levels should be measured when investigating possible islet cell tumors due to the effect of feeding on pancreatic function. Insulin measurements are particularly sensitive to hemolysis, and rapid processing to remove plasma from RBCs is optimal. Age-specific reference ranges are important for pancreatic polypeptide, as well as IGF-1.

Chromogranin A levels may be elevated because of proton pump inhibitor (PPI) administration, as well as renal or liver failure. A number of medications can cause an elevation in prolactin, including dopamine lowering agents (e.g., phenothiazines and reserpine), TRH, estrogens, H2-receptor blockers, and tricyclic antidepressants. Renal failure and circadian fluctuation also affect prolactin levels. For any analyte measured by radioimmunoassay, recent administration of radioactive material may interfere with the results.

What Lab Results Are Absolutely Confirmatory?

MEN1 gene mutations are the underlying molecular cause of this syndrome, and molecular genetic testing is, therefore, an absolute confirmation in the setting of the clinical syndrome. If the disease-causing mutation is identified for a given patient, this makes it possible to determine the risk of other family members. If a family member did not inherit the mutation, they are not at increased risk for development of the MEN1 syndrome and do not need additional screening laboratory testing. However, if family members inherited the MEN1 mutation, then they should be tested annually as described.

If it is not possible to identify the mutation but other family members manifest the disorder, it may be possible to determine whether an unknown member inherited the predisposing gene using genetic linkage analysis. If no genetic information can be obtained, it has been suggested that first-degree relatives should be followed with regular screening as though they were known to carry the mutation.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

As previously indicated, chromogranin A is a useful marker in the context of MEN1 screening for at-risk individuals. Chromogranin A marks neuroendocrine cells, but it may also be useful as an indication of a carcinoid tumor that may be associated with MEN1. If a patient is being referred for a parathyroidectomy, serial intraoperative PTH testing may help determine if the tumor has been adequately removed.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Parathyroid hormone measurements commonly detect multiple, different fragments of truly full-length PTH, and these fragments may have different half-lives in patients. Thus, for intraoperative testing, it is critical that the same analytical method be used for serial measurements of PTH. In the case of a possible insulinoma in which there is a concern about symptoms due to insulin administration, C-peptide can distinguish between endogenous (high C-peptide, high insulin) and exogenous (low C-peptide, high insulin) production.